The primary goal of this Program Project is to investigate interactions between the aging brain and female reproductive senescence. Early studies in young female rats demonstrated clearly that changes in circulating estrogen (E) levels affect cellular and molecular attributes of hypothalamic circuits as well as hippocampus, implicating E in modulating both reproductive neuroendocrine circuits and cognition. However, we now know that the aged brain reacts to E differently than the young brain, and we also know that the estrogen/aging interactions differ in important ways between rodents and nonhuman primates. The key to the next five years is to use both animal models to their best advantage to provide a neurobiological framework for the complex clinical issues surrounding the neurobiology of menopause and post-menopausal cognitive impairment. We will pursue a full spectrum analysis of the key issues; from signaling mechanisms of estrogen to an in-depth structural and functional assessment of the effects of estrogen on the circuits regulating reproductive function (hypothalamus), and cognition (hippocampus and prefrontal cortex). We will continue to reveal the neuronal signaling pathways activated by circulating E, as well as the molecular and synaptic basis for age related decline in E-induced synaptic plasticity. The rodent studies are particularly informative with respect to molecular mechanisms, and they have revealed several new targets of investigation for E signaling in hypothalamus, hippocampus and prefrontal cortex. The nonhuman primate studies reveal the neurobiological underpinnings of E-induced cognitive enhancement in aged monkeys, as well as the synaptic basis of cognitive resilience in the absence of E in young female monkeys. In addition, the nonhuman primate studies have highlighted the importance of prefrontal cortex and related cognitive functions as a target for E. Current studies in both the rat and nonhuman primate models are investigating the cognitive and neurobiological effects of different hormone treatment regimens. Proposed studies will investigate the window of opportunity hypothesis and the duration of beneficial effects after cessation of treatment. These results will provide critically important information on brain aging and will aid in the design of hormone treatments that provide maximal neurological benefits for post-menopausal women.